Objectives and Specific Aims Gammadelta T cells have unique features in comparison to alphabeta T cells. It has now become clear that gammadelta T cells recognize non- peptide and non-processed bacterial and environmental antigens, as well as stress-associated antigens expressed on epithelial cells and on certain tumor lines and primary carcinomas. However, understanding of gammadelta T cell biology has lagged behind that of alphabeta T cells. Recently, I have demonstrated that gammadelta T cells favor the Thl pathway of cytokine polarization, predominantly producing IFN-gamma. Furthermore, I have shown in my follow-up studies that the dominance of T-bet over GATA-3 leads to the default Thl-like pathway in gammadelta T cells. Based on these data, I hypothesize that gammadelat T cells play an important role in tumor immunity through their predominant production of IFN-gamma. To further address this hypothesis, I plan the following specific aims:
Aim 1. To further define the factors that modulate IFN-gamma production by gammadelta T cell in vitro. Here I will further characterize the molecular mechanisms of gammadelta T cell IFN-gamma production, focusing upon the balance between T-bet and GATA-3 in IFN-gamma production.
Aim 2. To define the role of IFN-gamma produced by gammadelta T cells in tumor immunity. Here I will define the role of IFN-gamma secreted solely by gammadelta T cells in a chemically-induced fibroscarcomas model. I will construct mice in which gammadelta T cells selectively lack the capacity to make IFN-gamma. Then I will challenge these mice with chemically-induced tumors.
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